European Journal of Neurology 2009, 16: 874–878
doi:10.1111/j.1468-1331.2009.02613.x
Peritumoral edema on MRI at initial diagnosis: an independent
prognostic factor for glioblastoma?
K. Schoeneggera,*, S. Oberndorfere,*, B. Wuschitze, W. Struhale, J. Hainfellnerb, D. Prayerc,
H. Heinzld, H. Lahrmanne, C. Marosia and W. Grisolde
a
Clinical Division of Oncology, Department of Medicine I, General Hospital, All Medical University of Vienna, Währinger Gürtel; bInstitute
of Neurology, General Hospital, All Medical University of Vienna, Währinger Gürtel; cDepartment of Radiology, General Hospital, All
Medical University of Vienna, Währinger Gürtel; dCore Unit for Medical Statistics and Informatics, General Hospital, All Medical University
of Vienna, Währinger Gürtel; and eLBI Neurooncology, KFJ-Hospital, Kundratstr, Vienna, Austria
Keywords:
glioblastoma, MRI, overall survival, peritumoral
brain edema, prognostic
factor
Received 9 September 2008
Accepted 18 February 2009
Background: Peritumoral brain edema in glioblastoma patients is a frequently
encountered phenomenon that strongly contributes to neurological signs and symptoms. The role of peritumoral edema as a prognostic factor is controversial.
Materials and Methods: This multi-centre clinical retrospective study included 110
patients with histologically proven glioblastoma. The prognostic impact on overall
survival of pre-treatment peritumoral edema detected on MRI-scans was evaluated.
All patients had preoperative MRI, surgery, histology, and received standard treatment regimens. Edema on MRI-scans was classified as minor (<1 cm), and major
(>1 cm).
Results: Our results confirm that peritumoral edema on preoperative MRI is an
independent prognostic factor in addition to postoperative Karnofsky performance
score (KPS), age, and type of tumor resection. Patients with major edema had significant shorter overall survival compared to patients with minor edema.
Conclusion: This easily applicable early radiological characterization may contribute
to a more subgroup oriented treatment in glioblastoma patients for future trials, as
well as in clinical routine.
Introduction
Glioblastoma is the most common malignant primary
brain tumor in adults. Prognosis of glioblastoma patients is dismal with a median survival of approximately
1 year [1,2]. However, patient outcome is variable with
a small fraction of long-term survivors [3,4]. To evaluate predictors of individual outcome in glioblastoma
patients, several clinical, radiological, molecular, and
histological factors have been identified. Important
factors are age, KPS (Karnofsky performance score),
extent of tumor resection, radio-chemotherapy, and
corticosteroid use [5–9]. Molecular alterations, such as
EGFR and MGMT promoter status are under investigation [10–12].
Peritumoral brain edema in glioblastoma patients is a
frequently encountered phenomenon. It is considered as
vasogenic; however, mechanisms of tumor related brain
Correspondence: Stefan Oberndorfer, MD, Department Neurology,
LBI Neurooncology, KFJ-Hospital, Kundratstr. 3, 1100 Vienna,
Austria (tel.: 00431601919992042; fax: 00431601912009; e-mail:
[email protected]).
*Both authors; contributed equally to the present investigation.
874
edema are complex and probably because of several
cellular mechanisms [13].
Its prognostic value at diagnosis, as well as in the
course of disease is still a matter of discussion. Peritumoral edema may cause severe neurological signs and
symptoms, and remains a challenge in the treatment of
glioblastoma patients. Some studies report that the
severity of brain edema at diagnosis is a negative
prognostic factor [14,15]. Other studies show no prognostic impact [7]. However, there is no agreement on
how peritumoral edema should be measured or classified on MRI-scans.
The purpose of this study was to evaluate the degree of
peritumoral edema as prognostic factor for survival in
glioblastoma patients. The peritumoral edema was
measured on first diagnostic MRI with an easy applicable and simple technique. Moreover, results from Pope
et al. [15], using a similar radiological technique for the
measurement of peritumoral edema, are re-evaluated.
Methods
This multi-centre retrospective study included 110
patients with primary glioblastoma. All patients
2009 The Author(s)
Journal compilation 2009 EFNS
Peritumoral edema GBM
underwent initial neurosurgical tumor intervention
between 1995 and 2005. Surgery was categorized as
total, subtotal, or biopsy. All tumor specimens were
histologically confirmed as glioblastomas according to
the WHO classification [1,2].
Postoperative KPS was assessed 10–14 days after
surgery [16]. Patients underwent standard treatment
with radio-chemotherapy.
The preoperative MRI-studies were performed at
different institutions. MRI scans had different slice
thicknesses and slice distances. However, minimum
protocol included axial T1-weighted sequences with and
without contrast enhancement, and a T2-weighted or
flair sequence for the assessment of edema and vascularity. Peritumoral edema was defined as a region of
increased T2 signal intensity on the tumor margin. In
most of the patients, axial scans were available, some
also had additional coronal sequences. If this was the
case, both axial and coronal sequences were analyzed.
Measurement was performed at the maximum extent of
the peritumoral edema evaluable on the MRI scans.
Edema extending <1 cm from the tumor margin was
defined as minor, and edema extending more than 1 cm
from the tumor margin as major (Fig. 1).
Tumor size was measured as unidimensional largest
diameter in cm on T2-weighted images. Two groups
were defined, using the mean value of 4.3 cm as cut-off
point (tumors £4 cm and tumors >4 cm). Contrast
875
enhancement – grading was not possible because of the
retrospective character of this study and the availability
of mostly hard copies. Moreover, different MRI
machines, contrast media, as well as application
schedules were applied.
Only treatment naive patients, with respect to antitumor and anti-edema therapy, were included. Steroid
use before first radiological diagnosis in a single patient
cannot be ruled out, but was not documented and
seems improbably prior to MRI confirmation of a
cerebral tumor mass.
The end-point of the study was overall survival,
which was measured from the day of surgery (equivalent to the day of diagnosis) until death of the patient.
Survival beyond the end of the observational period
(last follow-up visit) was considered as censored
observation.
Kaplan–Meier method was used to generate survival
plots. The prognostic value of the factors of interest was
assessed with Cox proportional hazards regression
models [17]. Overall and partial measures of dependence (R-squared values) were computed according to
Kent and OÕQuigley [18,19].
All reported P-values are results of two-sided tests.
P-values £0.05 were considered statistically significant.
All statistical analyses were performed using SPSS (SPSS
Inc., Chicago, IL, USA) or SAS (SAS Institute Inc.,
Cary, NC, USA).
(a)
< 1 cm
(b)
Figure 1 Measurement of peritumoral
edema by means of MRI T2 (coronal/axial) weighted images. (a) Coronal T2weighted images showing peritumoral
edema extending less than 1 cm from the
tumor margin, which was defined as minor
edema. (b) Axial T2-weighted images
showing peritumoral edema extending
more than 1 cm from the tumor margin as
major, which was defined as major edema.
2009 The Author(s)
Journal compilation 2009 EFNS European Journal of Neurology 16, 874–878
> 1 cm
876
K. Schoenegger et al.
Results
The main characteristics of the patients are summarized
in Table 1. Out of 110 patients, 71 (64.5%) were male
and 39 (35.5%) were female (gender ratio: 1.8). Fiftythree (48.2%) patients were £60 years and 57 (51.8%)
were >60 years (median age 60.1 years; range: 27.3–
84 years). During the observation period, 92 patients
died whilst 18 patients were still alive (follow up time
minimum 5 days, maximum 1354 days, median
293 days). Median postoperative KPS was 90% (range
50–100%). Eighty-three (85%) patients had a KPS ‡80
and 15 (15%) a KPS <80. In 12 cases, KPS was not
estimated. The MRIs of 24 (22%) patients showed
minor edema and in 86 (78%) patients, major edema.
Fifteen (14%) patients had biopsy only, 58 (53%) patients had subtotal, and 36 (33%) had total tumor
resection. In 56 patients, tumor size was measured.
Twenty-five (45%) patients had tumors £4 cm and 31
(55%) patients had tumors measuring >4 cm.
Eighty-four (77%) patients received radiotherapy
and adjuvant chemotherapy with alkylating agents.
Nine (8%) patients had radiotherapy, and one patient
chemotherapy only. Nine (8%) patients had surgical
tumor resection only. Out of these, one patient refused
any further treatment, three died shortly after surgery,
and four were included in the study after tumor resection and had not received any adjuvant treatment at
end-point. Six (5.5%) patients had biopsy only, and in
one case, information on adjuvant radio-chemotherapy
was not available.
Looking at the distribution of patient characteristics
in the edema subgroups, patients with minor edema
showed larger percentage of younger age and smaller
tumors. The percentage of patients receiving total,
subtotal resection, or biopsy is approximately equal in
both groups (Table 2). Correlation of factors showed a
weak correlation between edema grade and tumor
diameter (r = )0.33 P = 0.001). Between age-subgroups and KPS-subgroups, no significant correlation
could be found (r = )0.159 P = 0.117).
Table 2 Distribution of patient characteristics in edema subgoups
(absolute frequencies, percentages)
Factors of interest
Minor edema
Major edema
n = 24
15 (62.5%)
9 (37.5%)
n = 86
38 (44.2%)
48 (55.8%)
Age of patient (years)
£60
>60
Gender
n = 24
Female
12 (50%)
Male
12 (50%)
Karnofsky performance score
n = 19
<80
2 (10.5%)
‡80
17 (89%)
Tumor resection
n = 24
Total
8 (33.3%)
Subtotal
12 (50%)
Biopsy
4(16.7%)
Tumor size
n = 13
£4
9 (69.2%)
>4
4 (30.8%)
n = 86
27 (31.4%)
59 (68.6%)
n = 79
13 (16.5%)
66 (83.5%)
n = 85
28 (32.9%)
46 (54.1%)
11 (12.9%)
n = 43
16 (37.2%)
27 (62.8%)
Table 1 Patients characteristics are described with absolute frequencies, percentages and, if applicable, minimum and maximum values
Factors of interest
n
%
Age of patient (years) (Range 27.3–84.0, Median 60.1, Mean 58.7)
£60
53
48.2
>60
57
51.8
Gender
Female
39
35.5
Male
71
64.5
Karnofsky performance score (n = 98) (Range 50–100, Median 90)
<80
15
15.3
‡80
83
84.7
Edema
Minor edema (£1 cm)
24
21.8
Major edema (>1 cm)
86
78.2
Tumor resection (n = 109)
Total
36
33
Subtotal
58
53.2
Biopsy
15
13.8
Tumor size (cm) (n = 56) (Range 1.0–7.0, Median 5.0, Mean 4.3)
£4
25
44.6
>4
31
55.4
Figure 2 Kaplan–Meier estimated survival curves for the edema
subgroups (minor edema <1 cm and major edema >1 cm).
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Table 3 Hazard ratios, 95% confidence
intervals (CI), and P-values of four univariate and a multiple Cox model are given.
Partial adjusted R2 values are added for the
latter
Factors of interest
Univariate Cox models
Multiple Cox model
Hazard ratio
(95% CI)
Hazard ratio
(95% CI)
Age of patient
>60/£60
1.83 (1.21–2.77)
Karnofsky performance score
<80/‡80
3.26 (1.79–5.92)
Peritumoral edema
Major/minor
2.17 (1.23–3.80)
Tumor resection
Biopsy/total
2.98 (1.55–5.74)
Subtotal/total
0.87 (0.54–1.40)
Univariate analysis revealed that patients with major
edema had significantly shorter survival than patients
with minor edema (P = 0.006) (Fig. 2). A high KPS
(‡80%) (<0.0001) and younger age (£60 years)
(P = 0.004) were positive clinical factors, associated
with longer survival. Glioblastoma patients with biopsy
only had a significantly worse outcome as compared to
patients with total/subtotal resection (P = 0.0002).
Preoperative tumor size had no significant impact on
survival.
Multivariate analysis showed that postoperative KPS
>80, tumor resection, and minor edema on pre-treatment MRI are independently associated with longer
survival.
Adjusted R2 measure showed that these four prognostic factors explained 36.8% of the variability in the
overall survival time. The partial adjusted R2 for edema
alone after accounting for the effects of age, KPS, and
tumor resection was 11% (Table 3).
Discussion
Several studies have elaborated neuroradiological
imaging properties as prognostic factors in glioma patients. Tumor size, extent of necrosis, extent of peritumoral edema, contrast enhancement, location, and
others have been examined [20,21]. In a large series of
416 glioblastoma patients, Lacroix et al. found five
independent predictors: age, KPS, contrast enhancement, extent of necrosis on preoperative MRI, and
extent of resection. Extent of edema was not found to
be an independent prognostic factor in multivariate
analysis [7]. The evaluation of the extent of edema in
this series was modified and based on a study by
Hammoud et al. who introduced three edema grades
(grade I = amount of edema is less than tumor volume, grade II = amount of edema equal to tumor
volume, grade III = amount of edema is larger than
tumor volume) using volumetric data [14]. However,
Hammoud¢s study reported brain edema as significant
P-value
P-value
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Partial R2
0.004
1.54 (0.986–2.41)
0.058
2.9%
<0.0001
2.74 (1.48–5.08)
0.001
7.9%
0.006
2.51 (1.30–4.81)
0.006
11.0%
0.0002
4.90 (2.33–10.3)
0.87 (0.53–1.42)
<0.0001
17.6%
prognostic factor with the moderate edema group
having a significantly better outcome than the large
edema group. In conclusion: these two scoring systems
of peritumoral edema are bound to a time-consuming
procedure, and do not seem to yield data that is
reproducible.
In contrast, the evaluation system of peritumoral
edema in our study is measured in centimeter from the
outer ring of the tumor margin, followed by grouping
into a minor (<1 cm) and major (>1 cm) edema. A
similar scoring system for preoperative brain edema in
patients with high-grade gliomas was introduced by
Pope et al. They used imaging definitions with a clear
score description (0 = no edema, 1 = bright T2 signal
intensity with no mass effect and architectural deterioration and not extending more than 1 cm; 2 = edema
>1 cm) [15]. In this study, the extent of edema turned
out to be an independent prognostic factor in patients
with glioblastoma.
Thus, in the literature, results concerning the prognostic impact of brain edema in glioblastoma patients
have not been conclusive and uniform. Many different
scoring systems make comparison between studies and
validation of results difficult. Our study confirms the
results of Pope et al. applying a similar scoring system.
Both our and Pope et al.‘s [15] study establishes that
peritumoral edema is an independent prognostic factor
for survival in glioblastoma. The pathophysiological
mechanisms of pre-treatment peritumoral edema leading to a worse prognosis need to be elucidated in further
studies.
Extent of resection has a statistical significant impact
on overall survival. In this sample, we observed that
glioblastoma patients with biopsy had a significantly
worse outcome compared to patients with partial or
total resections. Comparing the patient subgroups with
partial and total resections, we did not find a significant
difference of outcome. This observation was previously
shared [22], whereas recent studies reported a better
outcome for patients with total resection [7,9]. This
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878
K. Schoenegger et al.
might be because of recently more accurate preand post-operative tumor volume measurements and
documentation.
Tumor size at first radiological diagnosis had no
significant impact on survival, as reported by Hammoud et al. [14], and Kreth et al. [22], although they
used different measurement techniques. We found that
larger tumors were more probably to have major edema
(Table 2). This positive weak correlation seems feasible,
but remains pathophysiologically unclear.
For use in everyday clinical setting, selection of
radiological parameters that are easily determined from
routine scans is preferable, whereas volumetric analysis
is bound to specific computer systems, and is a rather
time-consuming procedure. In this respect, we recommend this radiological scoring system for evaluation of
the extent of pre-treatment brain edema in glioblastoma. Our study confirms peritumoral edema as an
independent prognostic factor, as previously published
by Pope et al. [15]. This easily applicable early radiological characterization may contribute to a more subgroup oriented treatment approach in glioblastoma
patients for future trials as well as in clinical routine.
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